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Publication

Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis.

Cell stem cell | 2019

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis.

Pubmed ID: 30982771 RIS Download

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Associated grants

Agency: NINDS NIH HHS, United States
Id: R01 NS072427
Agency: NINDS NIH HHS, United States
Id: R01 NS078092
Agency: NINDS NIH HHS, United States
Id: R01 NS075243
Agency: NEI NIH HHS, United States
Id: R01 EY032029
Agency: NHLBI NIH HHS, United States
Id: R01 HL132211
Agency: NINDS NIH HHS, United States
Id: R37 NS096359

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This is a list of tools and resources that we have found mentioned in this publication.

R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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AltAnalyze - Alternative Splicing Analysis Tool (tool)

RRID:SCR_002951

Software application for microarry, RNA-Seq and metabolomics analysis. For splicing sensitive platforms (RNA-Seq or Affymetrix Exon, Gene and Junction arrays), it will assess alternative exon (known and novel) expression along protein isoforms, domain composition and microRNA targeting. In addition to splicing-sensitive platforms, it provides comprehensive methods for the analysis of other data (RMA summarization, batch-effect removal, QC, statistics, annotation, clustering, network creation, lineage characterization, alternative exon visualization, gene-set enrichement and more). AltAnalyze can be run through an intuitive graphical user interface or command-line and requires no advanced knowledge of bioinformatics programs or scripting. Alternative regulated exons can be subsequently visualized in the context of proteins, domains and microRNA binding sites with the Cytoscape Plugin DomainGraph.

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UCSC Genome Browser (tool)

RRID:SCR_005780

Portal to interactively visualize genomic data. Provides reference sequences and working draft assemblies for collection of genomes and access to ENCODE and Neanderthal projects. Includes collection of vertebrate and model organism assemblies and annotations, along with suite of tools for viewing, analyzing and downloading data.

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PeproTech (tool)

RRID:SCR_006802

An Antibody supplier

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MACS (tool)

RRID:SCR_013291

Software Python package for identifying transcript factor binding sites. Used to evaluate significance of enriched ChIP regions. Improves spatial resolution of binding sites through combining information of both sequencing tag position and orientation. Can be used for ChIP-Seq data alone, or with control sample with increase of specificity.

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SCDE (tool)

RRID:SCR_015952

Software package that implements a set of statistical methods for analyzing single-cell RNA-seq data, including differential expression analysis (Kharchenko et al.) and pathway and geneset overdispersion analysis (Fan et al.)

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Microsoft Excel (tool)

RRID:SCR_016137

Software application with data analysis tools and spreadsheet templates to track and visualize data. It is used to manage and process data.

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Slingshot (tool)

RRID:SCR_017012

Software R package for identifying and characterizing continuous developmental trajectories in single cell data. Cell lineage and pseudotime inference for single-cell transcriptomics.

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